Abstract

Aberrant activation of Anaplastic Lymphoma Kinase (ALK) has been described in a range of human cancers, including non-small cell lung cancer and neuroblastoma (Hallberg and Palmer 2013). Vertebrate ALK has been considered to be an orphan receptor and the identity of the ALK ligand(s) is a critical issue. Here we show that FAM150A and FAM150B are potent ligands for human ALK that bind to the extracellular domain of ALK and in addition to activation of wild type ALK are able to drive 'superactivation' of activated ALK mutants from neuroblastoma. In conclusion, our data show that ALK is robustly activated by the FAM150A/B ligands and provide an opportunity to develop ALK-targeted therapies in situations where ALK is overexpressed/activated or mutated in the context of the full length receptor.

Article and author information

Author details

  1. Jikui Guan

    Department of Medical Biochemistry and Cell Biology, Instititute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
    Competing interests
    The authors declare that no competing interests exist.
  2. Ganesh Umapathy

    Department of Medical Biochemistry and Cell Biology, Instititute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
    Competing interests
    The authors declare that no competing interests exist.
  3. Yasuo Yamazaki

    Department of Medical Biochemistry and Cell Biology, Instititute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
    Competing interests
    The authors declare that no competing interests exist.
  4. Georg Wolfstetter

    Department of Medical Biochemistry and Cell Biology, Instititute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
    Competing interests
    The authors declare that no competing interests exist.
  5. Patricia Mendoza

    Department of Medical Biochemistry and Cell Biology, Instititute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
    Competing interests
    The authors declare that no competing interests exist.
  6. Kathrin Pfeifer

    Department of Medical Biochemistry and Cell Biology, Instititute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
    Competing interests
    The authors declare that no competing interests exist.
  7. Ateequrrahman Mohammed

    Department of Medical Biochemistry and Cell Biology, Instititute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
    Competing interests
    The authors declare that no competing interests exist.
  8. Fredrik Hugosson

    Department of Medical Biochemistry and Cell Biology, Instititute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
    Competing interests
    The authors declare that no competing interests exist.
  9. Hongbing Zhang

    Five Prime Therapeutics Inc., South San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Amy W Hsu

    Five Prime Therapeutics Inc., South San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Robert Halenbeck

    Five Prime Therapeutics Inc., South San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Bengt Hallberg

    Department of Medical Biochemistry and Cell Biology, Instititute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
    Competing interests
    The authors declare that no competing interests exist.
  13. Ruth H Palmer

    Department of Medical Biochemistry and Cell Biology, Instititute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
    For correspondence
    ruth.palmer@gu.se
    Competing interests
    The authors declare that no competing interests exist.

Copyright

© 2015, Guan et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 3,395
    views
  • 821
    downloads
  • 118
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Jikui Guan
  2. Ganesh Umapathy
  3. Yasuo Yamazaki
  4. Georg Wolfstetter
  5. Patricia Mendoza
  6. Kathrin Pfeifer
  7. Ateequrrahman Mohammed
  8. Fredrik Hugosson
  9. Hongbing Zhang
  10. Amy W Hsu
  11. Robert Halenbeck
  12. Bengt Hallberg
  13. Ruth H Palmer
(2015)
FAM150A and FAM150B are activating ligands for Anaplastic Lymphoma Kinase
eLife 4:e09811.
https://doi.org/10.7554/eLife.09811

Share this article

https://doi.org/10.7554/eLife.09811

Further reading

    1. Cell Biology
    2. Developmental Biology
    Jeet H Patel, Mary C Mullins
    Insight

    Disease-causing mutations in the signaling protein BMP4 impair its secretion, but only when it is made as a homodimer.

    1. Cell Biology
    2. Genetics and Genomics
    Róża K Przanowska, Yuechuan Chen ... Anindya Dutta
    Research Article

    The six-subunit ORC is essential for the initiation of DNA replication in eukaryotes. Cancer cell lines in culture can survive and replicate DNA replication after genetic inactivation of individual ORC subunits, ORC1, ORC2, or ORC5. In primary cells, ORC1 was dispensable in the mouse liver for endo-reduplication, but this could be explained by the ORC1 homolog, CDC6, substituting for ORC1 to restore functional ORC. Here, we have created mice with a conditional deletion of ORC2, which does not have a homolog. Although mouse embryo fibroblasts require ORC2 for proliferation, mouse hepatocytes synthesize DNA in cell culture and endo-reduplicate in vivo without ORC2. Mouse livers endo-reduplicate after simultaneous deletion of ORC1 and ORC2 both during normal development and after partial hepatectomy. Since endo-reduplication initiates DNA synthesis like normal S phase replication these results unequivocally indicate that primary cells, like cancer cell lines, can load MCM2-7 and initiate replication without ORC.